ALKS 5461 is the combination of ALKS 33 and buprenorphine and is designed to be a non-addictive opioid modulator. ALKS 33 is an oral opioid modulator that builds on Alkermes’ scientific expertise in opioid biology and pharmacology, as well as the company’s clinical and commercial knowledge in the field of addiction and central nervous system disorders. ALKS 5461 is also in clinical development for the treatment of cocaine addiction, which is being funded through a grant from the National Institute on Drug Abuse (NIDA). In October 2013 , the FDA has granted Fast Track status for ALKS 5461 for the adjunctive treatment of MDD in patients with an inadequate response to standard therapies.

Disease: major depressive disorder (MDD)

Therapeutic
area: CNS diseases - Mental diseases

Country:

Trial
details:

The comprehensive pivotal program, named FORWARD (Focused On Results With A Rethinking of Depression), includes a total of 12 studies, including three core phase 3 efficacy studies and nine supportive studies. The program will evaluate the safety and efficacy of ALKS 5461 in patients suffering from MDD who have had an inadequate response to commonly prescribed drugs, including selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). The three core efficacy studies will utilize state-of-the-art methodologies to reduce the impact of clinically meaningful placebo response and are expected to randomize a total of approximately 1,500 patients with MDD who have had an inadequate response to standard therapies. The primary efficacy endpoint for the three core efficacy studies will be the change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) scores.

FORWARD-3 (NCT02158546) and FORWARD-4 (NCT02158533) are both phase 3, multinational, randomized, double-blind, placebo-controlled studies designed to evaluate the efficacy and safety of ALKS 5461 as adjunctive treatment in patients with MDD. The two studies combined are expected to randomize approximately 1,000 patients and incorporate sophisticated design features to ensure rigorous patient selection, monitoring and evaluation.

FORWARD-5 is a phase 3, multinational, randomized, double-blind, placebo-controlled, sequential parallel comparison design (SPCD) study that evaluated the safety, tolerability and efficacy of two dose levels of ALKS 5461 (2mg/2mg and 1mg/1mg) as adjunctive treatment in patients with MDD who had an inadequate response to a stable dose of either a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). The study randomized 407 subjects. The study was conducted in two sequential stages: Stage 1 was 5 weeks in duration, Stage 2 was 6 weeks. In Stage 1, the average change from baseline depression scores was calculated for weeks 3 through 5. For Stage 2, the average change was calculated for weeks 3 through 6. The results of Stages 1 and 2 were then averaged. Depression scores were assessed using the 6-item Montgomery-Åsberg Depression Rating Scale (MADRS-6) and MADRS-10. MADRS-6, a subscale of the MADRS-10 assessment tool for depression, focuses on the core symptoms of depression. (NCT02218008)

Latest
news:

• On October 29, 2018, Alkermes announced that Molecular Psychiatry has published phase 3 clinical data for ALKS 5461 (buprenorphine/samidorphan), a once-daily, oral investigational medicine that acts as an opioid system modulator and represents a novel mechanism of action for the adjunctive treatment of major depressive disorder (MDD) in patients with an inadequate response to standard antidepressant therapies. The publication includes comprehensive efficacy and safety results from FORWARD-4 (Study 205) and FORWARD-5 (Study 207), and a review of a pooled analysis of the two datasets. Collectively, ALKS 5461 demonstrated a consistent profile of antidepressant activity, safety and tolerability in the adjunctive treatment of MDD. Both studies utilized a sequential parallel-comparison design (SPCD), which includes two treatment stages and two randomizations in a single study to reduce the impact of placebo response commonly seen in psychiatric trials. SPCD builds on traditional placebo run-in designs, adding a randomly assigned active arm during the run-in phase to address treatment-related expectations and improve ascertainment of placebo non-response. The most common adverse events for ALKS 5461 in these studies included nausea, constipation, dizziness, vomiting, somnolence, fatigue and sedation. In these studies, ALKS 5461 showed low abuse potential and minimal evidence of dependence or opioid withdrawal as assessed by adverse events or the Clinical Opiate Withdrawal Scale (COWS).

The New Drug Application (NDA) for ALKS 5461 is currently under FDA review, with a FDA Advisory Committee meeting scheduled on Nov. 1, 2018 and a target action date of Jan. 31, 2019 . The NDA filing for ALKS 5461 is based on results from a clinical efficacy and safety package with data from more than 30 clinical trials and more than 1,500 patients with MDD.

• On October 20, 2016, Alkermes announced positive topline results from FORWARD-5, the third phase 3 efficacy study to read out from the FORWARD pivotal program for ALKS 5461 for the adjunctive treatment of major depressive disorder (MDD) in patients with an inadequate response to standard antidepressant therapies. The study met its prespecified primary endpoint showing treatment with ALKS 5461 significantly reduced symptoms of depression in patients with MDD compared to placebo. ALKS 5461 was generally well tolerated. The most common adverse events observed for ALKS 5461 were nausea, dizziness and fatigue. Based on these results, along with the substantial data collected to date on the efficacy and safety of ALKS 5461 for the treatment of MDD, the company plans to request a meeting with the FDA Division of Psychiatric Products to discuss the filing strategy for this Fast Track designated medicine.

The most commonly reported adverse events for ALKS 5461 in the FORWARD-5 study were nausea, dizziness and fatigue. These findings are consistent with those observed in previously reported studies of ALKS 5461. Alkermes will present comprehensive data from FORWARD-5 at an upcoming medical meeting and submit the results for publication in a peer-reviewed journal.

• On January 21, 2016, Alkermes announced preliminary topline results from FORWARD-3 and FORWARD-4, the first two of three phase 3 efficacy studies to read out from the comprehensive FORWARD pivotal program for ALKS 5461 for the adjunctive treatment of major depressive disorder in patients who have an inadequate response to standard therapies for clinical depression. Neither of the two studies met the prespecified primary efficacy endpoint, which compared ALKS 5461 to placebo on the change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS).

FORWARD-4 tested two dose levels of ALKS 5461 (2mg/2mg and 0.5mg/0.5mg) compared to placebo. 385 patients entered the study. There was a clear trend toward efficacy with the 2mg/2mg dose of ALKS 5461 on the primary endpoint, and post hoc analyses achieved statistical significance for the entire 2mg/2mg dose group on the MADRS endpoint. Based on these analyses, Alkermes believes that FORWARD-4 provides supportive evidence of the efficacy of ALKS 5461 in the treatment of major depressive disorder.

FORWARD-3 tested ALKS 5461 (2mg/2mg) compared to placebo. 429 patients entered the study. Placebo response was greater than that observed in FORWARD-4 and no treatment effect of ALKS 5461 was observed. Negative trials due to significant placebo effect are not uncommon in the study of major depressive disorder.

FORWARD-5, the third pivotal efficacy study in the FORWARD program, is ongoing, testing two dose levels of ALKS 5461 (2mg/2mg and 1mg/1mg). FORWARD-5 shares common design and analysis features with FORWARD-4. Based on information gained from FORWARD-3 and FORWARD-4, patient enrollment in FORWARD-5 will be increased and the statistical analysis plan will be updated. Alkermes will provide an update later this quarter on the projected timing of completion of FORWARD-5.

In the case of a clear positive outcome for FORWARD-5, Alkermes believes that the evidence provided by it and the previously completed successful, randomized, placebo-controlled phase 2 study, together with supportive evidence from FORWARD-4, collectively could provide substantial evidence of efficacy for ALKS 5461 for the adjunctive treatment of MDD. In that case, Alkermes would request a meeting with the FDA Division of Psychiatric Products to discuss the regulatory path for this Fast Track designated medicine.

In FORWARD-3, the most commonly reported adverse events were nausea, headache and fatigue, and in FORWARD-4 they were nausea, headache and dizziness. The safety and tolerability profile of ALKS 5461 was consistent with that reported for the phase 2 and FORWARD-1 studies.

• On July 30, 2014, Alkermes announced the initiation of FORWARD-5, the third of three core efficacy studies planned in the pivotal clinical program for ALKS 5461, for the adjunctive treatment of major depressive disorder (MDD). The study will evaluate the efficacy and safety of ALKS 5461 in patients suffering from MDD who have had an inadequate response to commonly prescribed drugs for depression, including selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Data from FORWARD-5, along with the two other core efficacy studies already underway, FORWARD-3 and FORWARD-4, are expected in 2016.

• On June 10, 2014, Alkermes announced the initiation of FORWARD-3 and FORWARD-4, two of the three planned phase 3 core efficacy studies in the pivotal clinical program for ALKS 5461. These studies will evaluate the efficacy and safety of ALKS 5461 in patients suffering from major depressive disorder who have had an inadequate response to commonly prescribed drugs, including selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Approximately two-thirds of patients who are diagnosed with MDD do not adequately respond to initial antidepressant therapy. Data from these two core efficacy studies are expected in 2016. FORWARD-5, the third core efficacy trial, is expected to initiate in mid 2014.

• On March 6, 2014, Alkermes has announced the initiation of the pivotal clinical development program for ALKS 5461, a once-daily, oral investigational medicine with a novel mechanism of action for the adjunctive treatment of major depressive disorder (MDD). The comprehensive pivotal program, named FORWARD (Focused On Results With A Rethinking of Depression), includes a total of 12 studies, including three core phase 3 efficacy studies and nine supportive studies. The first FORWARD study, evaluating the onset of clinical effect, safety and tolerability of ALKS 5461 in approximately 60 patients with MDD, has begun, and the three core efficacy studies are expected to begin in mid 2014.

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